CN112156064A - Paclitaxel oral dosage form and preparation method and application thereof - Google Patents
Paclitaxel oral dosage form and preparation method and application thereof Download PDFInfo
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Abstract
The disclosure belongs to the field of pharmacy, and particularly provides a paclitaxel oral dosage form as well as a preparation method and application thereof. The oral paclitaxel dosage form comprises paclitaxel and antarctic krill oil. The preparation method of the paclitaxel oral dosage form comprises the following steps: adding paclitaxel powder into anhydrous ethanol, and sufficiently shaking to dissolve to obtain paclitaxel ethanol solution; adding paclitaxel ethanol solution into Euphausia superba oil stock solution, mixing, and shaking on a constant temperature shaking table until ethanol is completely volatilized. The problems that liposome paclitaxel in the prior art is low in entrapment rate, easy to leak, and capable of inducing an organism to generate complement reaction and the like are solved, the clinical application of the liposome paclitaxel is limited, and an ideal anti-tumor effect is difficult to achieve through oral administration of a paclitaxel administration system.
Description
Technical Field
The disclosure belongs to the field of pharmacy, and particularly provides a paclitaxel oral dosage form as well as a preparation method and application thereof.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Paclitaxel (Paclitaxel PTX), also known as taxol, was originally isolated from the bark of Taxus brevifolia (Taxus brevifolia), a novel antimicrotubule drug approved by the U.S. Food and Drug Administration (FDA) for marketing in 1992. Paclitaxel is a broad-spectrum anticancer drug, and has been widely used for clinical treatment of ovarian cancer, breast cancer, head and neck cancer and lung cancer, and the main action mechanisms of paclitaxel are promoting microtubule polymerization of cells, inhibiting microtubule depolymerization, causing cell spindle to lose normal function, arresting cell cycle in G2/M phase, and stopping mitosis. Because paclitaxel is difficult to dissolve in water, anhydrous ethanol and polyoxyethylene castor oil (1:1) are used as cosolvent carriers in the existing preparation formula, which can cause patients to have serious adverse reactions such as anaphylactic reaction, renal toxicity and the like, thereby limiting the clinical application of the preparation.
In order to improve the solubility of paclitaxel in water, reduce the occurrence of toxic and side effects and improve the antitumor activity of paclitaxel, scholars at home and abroad make extensive studies on different drug-loading systems, preparation formulations, clinical medication modes and the like of paclitaxel. The paclitaxel which is marketed at home has the innovative formulations of liposome paclitaxel, albumin paclitaxel and the like, thereby obviously reducing the side effect of the traditional formulation and bringing more choices for cancer patients. The albumin paclitaxel is approved by the FDA in 2005 to be marketed, the curative effect of the paclitaxel can be improved on the basis of no increase of toxic and side effects, but the overall price of the albumin paclitaxel is higher than that of the conventional dosage form, and adverse reactions such as neurotoxicity and the like exist when the intake is increased, and the clinical application of the albumin paclitaxel is limited due to the risk of infecting blood-borne diseases. The liposome paclitaxel is approved to be applied to the clinical tumor treatment in China in 2010 and can improve the effect of the paclitaxel, but the inventor finds that the liposome paclitaxel has the problems of low entrapment rate, easy leakage of the paclitaxel, induction of the body to generate complement reaction and the like, and limits the clinical application of the liposome paclitaxel. The paclitaxel administration system is difficult to achieve ideal anti-tumor effect after oral administration.
Antarctic krill (Antarctic krill) is a krill living in Antarctic waters, takes tiny phytoplankton as food, is one of single organisms with the largest resource quantity at present on the earth, and has great development and utilization potential. The antarctic krill oil is extracted from wild antarctic krill in the antarctic sea area, contains a large amount of phospholipids, omega-3 (EPA, DHA) polyunsaturated fatty acids and astaxanthin, also contains active substances such as vitamin A, D, E, animal flavonoid, chitin, trace elements and the like, and is safe and free of toxic and side effects.
Disclosure of Invention
Aiming at the problems of low entrapment rate, easy leakage of paclitaxel, body induction to generate complement reaction and the like of liposome paclitaxel in the prior art, the clinical application of the liposome paclitaxel is limited, and the ideal anti-tumor effect is difficult to achieve by oral administration of a paclitaxel administration system.
In one or more embodiments of the present disclosure, a paclitaxel oral dosage form is provided, comprising paclitaxel and antarctic krill oil.
In one or some embodiments of the present disclosure, there is provided a method for preparing a paclitaxel oral dosage form, comprising the steps of: the ethanol solution of the paclitaxel is 8-11mg/mL, preferably 10 mg/mL; further preferably, the weight of paclitaxel is 100mg, the volume of absolute ethanol is 10mL, and the concentration of the ethanol solution of paclitaxel is 10 mg/mL.
In one or more embodiments of the present disclosure, there is provided an application of the paclitaxel oral dosage form or the product prepared by the preparation method of the paclitaxel oral dosage form in preparing a drug for treating tumor.
In one or more embodiments of the present disclosure, there is provided an application of the paclitaxel oral dosage form or the product prepared by the preparation method of the paclitaxel oral dosage form in preparing a drug for treating ovarian cancer.
In one or more embodiments of the present disclosure, there is provided an application of the paclitaxel oral dosage form or the product prepared by the preparation method of the paclitaxel oral dosage form in preparing a drug for treating ovarian cancer tumor.
One or some of the above technical solutions have the following advantages or beneficial effects:
1) according to the preparation method, the paclitaxel is directly mixed with the antarctic krill crude oil for preparation, the preparation method is simple, and from experimental results, the effect of mixing the paclitaxel and the antarctic krill crude oil is good, one side of the mixture is good in that the paclitaxel can be well dissolved in the antarctic krill crude oil, the mixing performance of two systems is good, the other side of the mixture is good in that the antarctic krill oil can exert the pharmacodynamic value of the paclitaxel to the maximum extent, and particularly, the preparation method has a good treatment effect in terms of resisting ovarian cancer tumors.
2) The antarctic krill oil and the mixed oil system are compared, and the result shows that the paclitaxel in the mixed oil system has a good dissolving effect but a poor drug effect, so that the compatibility relationship exists between the antarctic krill oil and the paclitaxel.
Drawings
FIG. 1 is a graph of the inhibition rate of krill oil-paclitaxel drug system against A2780 cells in example 2.
Fig. 2 is a graph of the inhibition rate of krill oil-paclitaxel drug system against SKOV3 cells in example 2.
FIG. 3 is a graph of the effect of the krill oil-paclitaxel drug system on the cell cycle of A2780 cells in example 2. P < 0.001.
Fig. 4 is a graph of the effect of the krill oil-paclitaxel drug system on the cell cycle of SKOV3 in example 2. P < 0.001.
FIG. 5 is a graph of the effect of the krill oil-paclitaxel drug system on tumor weight in SKOV3 tumor-bearing mice in example 3. P <0.05, P < 0.01.
Detailed Description
The technical solutions in the embodiments of the present disclosure will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present disclosure, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the disclosure without making any creative effort, shall fall within the protection scope of the disclosure.
Aiming at the problems of low entrapment rate, easy leakage of paclitaxel, body induction to generate complement reaction and the like of liposome paclitaxel in the prior art, the clinical application of the liposome paclitaxel is limited, and the ideal anti-tumor effect is difficult to achieve by oral administration of a paclitaxel administration system.
The invention aims to prepare a antarctic krill oil and paclitaxel drug system, and aims to break through the limitation of adverse reactions of the current clinical paclitaxel dosage forms, change the dosage form of paclitaxel, change the prior paclitaxel which can only be administered by injection into oral administration, further improve the bioavailability and the antitumor activity of the paclitaxel, greatly reduce the toxic and side effects, reduce the dosage, reduce the treatment cost and be more beneficial to the treatment of cancers.
In one or more embodiments of the present disclosure, a paclitaxel oral dosage form is provided, comprising paclitaxel and antarctic krill oil.
Preferably, the paclitaxel is dispersed in the antarctic krill oil. Specifically, paclitaxel and antarctic krill oil can be fully mixed in a liquid state, and the two are mixed to obtain the composition. However, in theory, paclitaxel and antarctic krill oil have an interaction promoting effect, and if the paclitaxel and antarctic krill oil are in a core-shell structure, the paclitaxel and antarctic krill oil can be prepared into an oral dosage form as long as the particle size is small enough.
In one or some embodiments of the present disclosure, there is provided a method for preparing a paclitaxel oral dosage form, comprising the steps of: adding paclitaxel powder into anhydrous ethanol, and sufficiently shaking to dissolve to obtain paclitaxel ethanol solution; adding paclitaxel ethanol solution into Euphausia superba oil stock solution, mixing, and shaking on constant temperature shaking table until ethanol is completely volatilized.
The addition of the ethanol is beneficial to fully mixing the paclitaxel and the antarctic krill oil, the paclitaxel and the antarctic krill have phase interfaces after mixing due to two different components, and the paclitaxel and the antarctic krill oil are mixed and melted in the mixing and volatilizing process after the ethanol is added, so that the paclitaxel and the antarctic krill oil are fully mixed. It should be noted that since the evaporation rate of ethanol affects the phase interface between paclitaxel and antarctic krill oil, constant temperature evaporation should be performed to avoid imbalance of the phase interface due to the change of the ethanol rate.
The Antarctic krill oil can be sold in the market or extracted by self.
Preferably, the ethanol solution of the paclitaxel is 8-11mg/mL, and preferably 10 mg/mL; further preferably, the weight of paclitaxel is 100mg, the volume of absolute ethanol is 10mL, and the concentration of the ethanol solution of paclitaxel is 10 mg/mL.
The concentration and the addition amount of the absolute ethyl alcohol should be proper, because if the addition amount of the absolute ethyl alcohol is too large, the interface compatibility of the paclitaxel and the antarctic krill oil is too large, the drug effect of the paclitaxel is poor, and if the addition amount of the absolute ethyl alcohol is too small, the interface is not dissolved, so that the effect of the oral preparation is difficult to achieve.
Preferably, the volume ratio of the stock solution of the Antarctic krill oil to the absolute ethyl alcohol is 1-2:1-2, preferably 1: 1; as in the above case, the ratio of absolute ethanol to Antarctic krill oil should be appropriate.
Preferably, the constant temperature shaking table is 30-40 ℃, preferably 37 ℃. Because the optimal temperature of the human body is 37 ℃, the absorption of the human body is most suitable under the condition of 37 ℃, the anhydrous ethanol and the antarctic krill oil are stirred at 37 ℃, and the absorption rate of the human body is greatly promoted.
Preferably, the shaking time is 10 to 15 hours, preferably 12 hours.
In one or more embodiments of the present disclosure, there is provided an application of the paclitaxel oral dosage form or the product prepared by the preparation method of the paclitaxel oral dosage form in preparing a drug for treating tumor.
In one or more embodiments of the present disclosure, there is provided an application of the paclitaxel oral dosage form or the product prepared by the preparation method of the paclitaxel oral dosage form in preparing a drug for treating ovarian cancer.
According to the application, the A2780 cells and the SKOV3 cells, namely different human ovarian cancer cells, are respectively used for testing, and from the test result, the drug system disclosed by the application has a good inhibition rate on the human ovarian cancer cells, so that the therapeutic mechanism of the antarctic krill oil-paclitaxel drug system on ovarian cancer is that the drug system is an inhibitor of the A2780 cells and the SKOV3 cells.
In one or more embodiments of the present disclosure, there is provided an application of the paclitaxel oral dosage form or the product prepared by the preparation method of the paclitaxel oral dosage form in preparing a drug for treating ovarian cancer tumor.
The disclosure performs cell periodic tests, and from the test results, the pharmaceutical system disclosed by the disclosure can block ovarian cancer cells in the G2/M phase, inhibit cell proliferation and thus inhibit the activity of the ovarian cancer cells.
Example 1
This example provides a method for preparing an oral dosage form of paclitaxel, comprising the steps of:
adding 100mg of paclitaxel powder into 10mL of absolute ethanol, and fully shaking to dissolve to prepare 10mg/mL of paclitaxel ethanol solution; and adding the ethanol solution of the paclitaxel into 10mL of antarctic krill oil stock solution, uniformly mixing, fully oscillating on a constant-temperature shaking table at 37 ℃ for 12 hours, and forming a stable antarctic krill oil-paclitaxel medicine system after the ethanol is completely volatilized.
The experimental result shows that the appearance of the successfully prepared antarctic krill oil-paclitaxel medicine system is clear and transparent, is similar to that of the single antarctic krill oil, and has no precipitation, and the system is stable and has no obvious precipitation after being placed at room temperature for 24 hours.
Comparative example 1
This example provides a method for preparing an oral paclitaxel formulation, which differs from example 1 in that the euphausia superba oil is replaced with soybean phospholipids.
The experimental result shows that in the successfully prepared soybean phospholipid-paclitaxel drug system, the paclitaxel in a bulk shape can be seen to be suspended in the soybean phospholipid, no precipitate is separated out, and the system is stable and no obvious precipitate is separated out after being placed for 24 hours at room temperature.
As can be seen from the comparison of comparative example 1 with example 1, the scheme using soybean phospholipids had poor solubility of paclitaxel, and the inventors considered that the reason may be that the interfacial solubility of paclitaxel ethanol solution with soybean phospholipids was poor.
Comparative example 2
This example provides a method for preparing an oral paclitaxel formulation, which is different from example 1 in that the antarctic krill oil is replaced by a mixture of soybean phospholipids and cholesterol, and the mixture is mixed by an ultrasonic device.
Experimental results show that the prepared mixed oil-paclitaxel medicine system is clear and transparent, is similar to the single mixed oil, and has no precipitation, and the system is stable and has no obvious precipitation after being placed at room temperature for 24 hours.
As can be seen from the comparison between comparative example 2 and example 1, the solubility of the compounded mixed oil phase is better, and the inventor thinks that the reason is probably that the density of the mixed oil phase is similar to that of the paclitaxel ethanol solution.
Example 2
This example provides an in vitro cell assay of Euphausia superba oil-paclitaxel drug System
(1) SRB in vitro cell proliferation assay
Ovarian cancer cells in logarithmic growth phase, SKOV3, were seeded in 96-well plates (approximately 3000 cells/well) and incubated in a 5% CO2, 37 ℃ incubator. After 24 hours, the original culture medium was discarded from each well, 1,2, 5, 10, 20, 50, 100nM of the Euphausia superba oil-paclitaxel drug system was added, and the control group was given the same concentration of Euphausia superba oil and incubated in an incubator for 3 days. The cell culture supernatant was removed and the cells were fixed for 1 hour at 4 ℃ with the addition of pre-cooled 10% trichloroacetic acid. The fixative was removed and the wells were air dried after 5 washes with distilled water. After drying, 100. mu.L of 0.4% SRB solution was added to each well and stained for 30 minutes. The dye solution was removed, washed 5 times with 1% glacial acetic acid solution and air dried. The bound SRB was dissolved sufficiently in Tris buffer (150. mu.L, 10mM), and the OD value of each group was measured in an enzyme-linked immunosorbent assay to calculate the inhibition rate of the drug on the growth of tumor cells.
As shown in fig. 1 and 2, the experimental results show that the tumor cell growth inhibition rate of the group administered with the antarctic krill oil-paclitaxel drug system is obviously increased compared with that of the group administered with the antarctic krill oil alone.
(2) Cell cycle assay
Ovarian cancer cells in logarithmic growth phase SKOV3 were seeded in 6-well plates (approximately 1 × 105 cells/well) and incubated in a 5% CO2, 37 ℃ incubator. After 24 hours, 20nM and 50nM antarctic krill oil-paclitaxel drug system and antarctic krill oil stock solution were added, respectively, and incubation was continued for 24 hours. The cells were harvested, washed 3 times with PBS by centrifugation, resuspended in a-20 ℃ pre-chilled 70% ethanol solution for 2 hours, and washed 2 times with PBS by centrifugation. The washed cells were incubated with 200. mu.g/mL RNase at room temperature for 30 minutes, and finally with 50. mu.g/mL PI solution at 4 ℃ for 30 minutes. The treated cells were detected in a flow cytometer by standard procedures and the proportion of cells in different cell cycles was analyzed to evaluate the mechanism of action of the antarctic krill oil-paclitaxel drug system in inhibiting cell proliferation.
As shown in fig. 3 and 4, the experimental results show that the proportion of cells in the cell cycle of tumor cells in the group of the antarctic krill oil-paclitaxel drug system is obviously increased in the G2/M phase compared with the antarctic krill oil alone.
Example 3
This example provides an in vivo anti-tumor experiment of Euphausia superba oil-paclitaxel drug system
Healthy female bare BABL/C mice were selected as 18 mice, randomly and equally divided into 3 groups, and freely fed and drunk water. Injecting human ovarian cancer cell SKOV3 into mouse axilla to construct human ovarian cancer nude mouse model. In 2 weeks after molding, one group of mice was gavaged with physiological saline, one group was gavaged with antarctic krill oil at a dose of 0.2 ml/mouse, the other group was gavaged with a dose of 20mg/kg final concentration of paclitaxel to administer an antarctic krill oil-paclitaxel drug system, the concentration of the system was also adjusted to a dose of 0.2 ml/mouse of antarctic krill oil, once daily, two weeks after continuous administration, the mice were sacrificed, and the antitumor effects of the drug delivery systems were evaluated by comparing the tumor weights of three groups of tumor-bearing mice.
As shown in fig. 5, the experimental results show that the average tumor weight of the normal saline group is 0.5627g, the average tumor weight of the antarctic krill oil group is 0.5497g, the average tumor weight of the antarctic krill oil-paclitaxel drug system group is 0.4554g, the average tumor weight of the comparative example 1 group is 0.5344g, and the average tumor weight of the comparative example 2 group is 0.5438 g.
The mice administered with the antarctic krill oil-paclitaxel drug system group had significantly inhibited ovarian cancer tumor growth compared to the normal saline group and the antarctic krill oil group alone. The result shows that the antarctic krill oil-paclitaxel drug system has obvious antitumor activity.
The disclosure of the present invention is not limited to the specific embodiments, but rather to the specific embodiments, the disclosure is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. An oral paclitaxel dosage form is characterized by comprising paclitaxel and antarctic krill oil.
2. The oral dosage form of paclitaxel according to claim 1, wherein the paclitaxel is dispersed in antarctic krill oil.
3. A method for preparing a paclitaxel oral dosage form is characterized by comprising the following steps: adding paclitaxel powder into anhydrous ethanol, and sufficiently shaking to dissolve to obtain paclitaxel ethanol solution; adding paclitaxel ethanol solution into Euphausia superba oil stock solution, mixing, and shaking on constant temperature shaking table until ethanol is completely volatilized.
4. The method of preparing a paclitaxel oral dosage form according to claim 3, wherein the ethanol solution of paclitaxel is 8-11mg/mL, preferably 10 mg/mL; further preferably, the weight of paclitaxel is 100mg, the volume of absolute ethanol is 10mL, and the concentration of the ethanol solution of paclitaxel is 10 mg/mL.
5. The method for preparing paclitaxel oral dosage form according to claim 3, wherein the volume ratio of the stock solution of Antarctic krill oil to absolute ethanol is 1-2:1-2, preferably 1: 1.
6. The process for the preparation of an oral dosage form of paclitaxel according to claim 3, wherein the temperature is maintained in a constant temperature shaker at 30-40 ℃, preferably 37 ℃.
7. The process for the preparation of an oral dosage form of paclitaxel according to claim 3, wherein the shaking time is 10-15 hours, preferably 12 hours.
8. Use of the product of the paclitaxel oral dosage form according to claim 1 or 2 or the method of any of claims 3-7 for the preparation of a medicament for the treatment of tumors.
9. Use of a product obtained by the method of preparation of a paclitaxel oral dosage form according to claim 1 or 2 or a paclitaxel oral dosage form according to any of claims 3-7 for the manufacture of a medicament for the treatment of ovarian cancer.
10. Use of the paclitaxel oral dosage form according to claim 1 or 2 or the product obtained by the method for preparing the paclitaxel oral dosage form according to any one of claims 3 to 7 in the preparation of a medicament for treating ovarian cancer tumors.
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| EP2957290A1 (en) * | 2014-06-19 | 2015-12-23 | Pharco | Krill oil and turmeric extract-based composition |
| CN105920052A (en) * | 2016-05-10 | 2016-09-07 | 胡铭 | Red yeast rice and euphausia superba oil soft capsule composition having function of reducing blood fat |
| US20170182073A1 (en) * | 2014-02-12 | 2017-06-29 | Aker Biomarine Antarctic As | Capsules containing high doses of krill phospholipids |
| CN108041184A (en) * | 2017-12-20 | 2018-05-18 | 山东朱氏药业集团有限公司 | A kind of compound lard for preventing and treating angiocardiopathy |
| WO2019170284A1 (en) * | 2018-03-07 | 2019-09-12 | Athenion Ag | Krill oil for solubilizing poorly water-soluble dietary supplements and pharmaceutically active agents |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170182073A1 (en) * | 2014-02-12 | 2017-06-29 | Aker Biomarine Antarctic As | Capsules containing high doses of krill phospholipids |
| EP2957290A1 (en) * | 2014-06-19 | 2015-12-23 | Pharco | Krill oil and turmeric extract-based composition |
| CN105920052A (en) * | 2016-05-10 | 2016-09-07 | 胡铭 | Red yeast rice and euphausia superba oil soft capsule composition having function of reducing blood fat |
| CN108041184A (en) * | 2017-12-20 | 2018-05-18 | 山东朱氏药业集团有限公司 | A kind of compound lard for preventing and treating angiocardiopathy |
| WO2019170284A1 (en) * | 2018-03-07 | 2019-09-12 | Athenion Ag | Krill oil for solubilizing poorly water-soluble dietary supplements and pharmaceutically active agents |
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